Circulating tumor cells (CTCs) dynamics after CDK4/6i for hormone-receptor positive (HR+) metastatic breast cancer (MBC): A biomarker analysis of the PACE randomized phase II study.
Authors: Lorenzo Gerratana, Yue Ren, Carolina Reduzzi, Meredith M. Regan, Reshma L. Mahtani, Cynthia X. Ma, Angela DeMichele, Jane Lowe Meisel, Kathy Miller, Trevor Augustus Jolly, Elizabeth Carloss Riley, Rubina Qamar, Priyanka Sharma, Sonya A. Reid, Naomi Yu Ko, Yuan Liu, Harold J. Burstein, Sara M. Tolaney, Massimo Cristofanilli, Erica L. Mayer
Journal: Journal of Clinical Oncology (2023)

1059 Background: PACE is a multicenter randomized phase II trial investigating palbociclib (P) in combination with fulvestrant (F) after progression on any CDK4/6 inhibitor (CDK4/6i), with or without the PD-L1 inhibitor avelumab (A), in HR+/HER2- MBC. CTCs are rare cells in the blood stream whose detection is associated with worse outcome and treatment resistance. Methods: Eligible patients (pts) had HR+/HER2- MBC with prior progression after ≥ 6 months (mo) of AI and CDK4/6i for MBC, or during/within 12 mo in the adjuvant setting, with ≤ 1 prior chemotherapy for MBC. Pts were randomized 1:2:1 to F, F+P, or F+P+A. CTC detection and enumeration were performed utilizing CellSearch (Menarini Silicon Biosystems) at baseline (BL), at time of first tumor assessment (TTA1), and at progression. Results were dichotomized using the standard CTC threshold (≥ 5 CTCs/7.5 ml) into a novel prognostic classification: StageIV indolent and StageIV aggressive (Cristofanilli et al 2019). Concurrent ctDNA Sequencing was performed using Guardant360 (Guardant Health). Results: Of the 220 randomized pts, 203 (92%) had sample available for BL CTC enumeration, 155 had detectable CTCs (70.5%), and 99 (48.8%) were StageIV aggressive . De novo disease at initial diagnosis was associated with StageIV aggressive (47.5% vs 30.8% StageIV indolent ), and distribution of visceral versus non-visceral disease was similar across the two CTCs groups. StageIV aggressive represented 38.3%, 54.8%, and 46.2% of the F, F+P and F+P+A treatment groups, respectively. BL CTCs were prognostic in the overall cohort; median PFS was 5.7mo vs 3.5mo for StageIV indolent vs StageIV aggressive (HR: 1.69, 90%CI 1.27,2.24, P&lt;0.001). Median PFS for the F, F+P and F+P+A arms was 1.9mo, 4.6mo and 5.4mo in StageIV aggressive compared to 8.2mo, 5.3mo and 8.3mo in StageIV indolent . Among patients in the StageIV aggressive subgroup, the F+P and F+P+A arms demonstrated improved outcomes compared to F alone. (F+P vs F HR 0.43, 90% CI 0.25-0.71, and F+P+A vs F HR 0.26, 90% CI 0.14-0.49). No benefit of F+P or F+P+A over F was observed in the StageIV indolent subgroup (F+P vs F HR 1.45, 90% CI 0.87 - 2.40 and F+P+A vs F HR 1.06, 90% CI 0.61 - 1.84, each p(interaction)&lt;0.01). Changes in StageIV CTC characterization (indolent vs aggressive) between BL and TTA1 among the subset of 175/203 pts with both timepoints available are reported. Conclusions: Baseline CTC enumeration is prognostic in patients receiving F with or without CDK4/6i. The StageIV aggressive subgroup may derive preferential benefit with combinations of F+P or F+P+A over F alone. Findings should be confirmed in other studies. ctDNA analyses are ongoing. Clinical trial information: NCT03147287 . [Table: see text]